The composition of the gut microbiome has been implicated in health and disease. However, how the microbiome interacts with the nervous system remains poorly understood. Animals contain diverse bacterial strains in their gut microbiome that influence many processes such as host metabolism and immune defense. Recent studies have also shown that neurological diseases are correlated with a differential microbiome compared to healthy controls. But how the composition of the gut microbiome can influence neuronal function and neurological disease etiology is still poorly understood. In this project, I will determine how diverse bacteria, that are both beneficial and detrimental to overall animal health, signal to the nervous system and ultimately contribute to behavior. I will uncover new molecular mechanisms by which the gut microbiome signals to the nervous system and alters neuronal function. I will also examine how this signaling influences neural circuit function and behavior. To permit unbiased identification of novel molecular pathways, I will perform these studies in C. elegans, a model organism that has been a vital tool in biology for the discovery of fundamental molecular pathways that operate in neurons. The nematode C. elegans eat bacteria as their food source and wild C. elegans contain a diverse microbiome with many bacterial species shared with the human microbiome. In the lab, we are easily able to control the composition of the C. elegans microbiome and, using genetic tools, we can monitor calcium dynamics in individual neurons and behavioral changes as animals respond to new strains of bacterial food. I now propose to identify the specific signaling molecules, receptors and neuronal pathways that allow gut bacteria to influence C. elegans behavior. Specifically, in Aim 1, I will determine the molecular signal from bacteria that directly stimulates ASIC channels in an enteric sensory neuron called NSM that extends a sensory ending into the alimentary canal. These studies will reveal precise bacterial signal(s) that can be detected by neurons to influence nervous system function. In Aim 2, I will identify receptors required to detect signals from the gut in interoceptive neurons that are poised to detect hormones and metabolites released by the gut. Altogether, these studies will illuminate fundamental molecular and cellular pathways that control gut- brain communication, with direct implications for diseases that are associated with alterations in the gut microbiome.